C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPβ.

C/EBP beta is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBP gamma, a heterodimeric partner of C/EBP beta whose biological functions are not well understood, inhibits cellular senescence. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferated poorly, entered senescence prematurely, and expressed a proinflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBP beta. The senescence-suppressing activity of C/EBP gamma required its ability to heterodimerize with C/EBP beta. Covalently linked C/EBP beta homodimers (beta similar to beta) inhibited the proliferation and tumorigenicity of Ras(V12)-transformed NIH 3T3 cells, activated SASP gene expression, and recruited the CBP coactivator in a Ras-dependent manner, whereas gamma similar to beta heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg(-/-) MEFs. C/EBP beta depletion partially restored growth of C/EBP gamma-deficient cells, indicating that the increased levels of C/EBP beta homodimers in Cebpg(-/-) MEFs inhibit proliferation. The proliferative functions of C/EBP gamma are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg(-/-) bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBP gamma depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBP gamma neutralizes the cytostatic activity of C/EBP beta through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.